Showing papers by "Hisashi Yamamoto published in 2022"

Protective Effect of D-Alanine Against Acute Kidney Injury.

Abstract: BACKGROUND Recent studies revealed the connection between amino acid chirality and diseases. We previously reported that the gut microbiota produced various D-amino acids in a murine acute kidney injury (AKI) model. Here, we further explore the pathophysiological role of D-Alanine (Ala) in AKI. METHODS We analyzed the transcripts of the N-methyl-D-aspartate (NMDA) receptor, a receptor for D-Ala, in tubular epithelial cells (TECs). Then, the therapeutic effect of D-Ala was assessed in vivo and in vitro. Lastly, the plasma level of D-Ala was evaluated in AKI patients. RESULTS The Grin genes encoding NMDA receptor subtypes were expressed in TECs. Hypoxia condition changes the gene expressions of Grin1, Grin2A and Grin2B. D-Ala protected TECs from hypoxia-related cell injury and induced proliferation after hypoxia. These protective effects are associated with the chirality of D-Ala. D-Ala inhibits ROS production and improves mitochondrial membrane potential, through NMDA receptor signaling. The ratio of D-Ala/L-Ala was increased in feces, plasma, and urine after the induction of I/R. Moreover, enterobacteriaceae, such as Escherichia coli, Klebsiella oxytoca produced D-Ala. The oral administration of D-Ala ameliorated kidney injury after I/R induction in mice. The deficiency of NMDA subunit NR1 on tubular cell worsened kidney damage in AKI. In addition, the plasma level of D-Ala was increased and reflected the level of renal function in AKI patients. CONCLUSIONS D-Ala has protective effects on I/R-induced kidney injury. Moreover, the plasma level of D-Ala reflects the eGFR in AKI patients. D-Ala could be a promising therapeutic target and potential biomarker for AKI.

Synthesis of Silacyclic Dipeptides: Peptide Elongation at Both N- and C-Termini of Dipeptide.

Abstract: A new type of peptide bond formation utilizing silacyclic amino acids or peptides is described. This work has the following advantages: (1) imidazolylsilane is a highly fascinating coupling reagent for dipeptide synthesis from N-,C-terminal unprotected amino acids with amino acid tert-butyl esters; (2) deprotection of the tert-butyl ester at the C-terminus and cyclization sequentially proceed depending on reaction conditions to afford novel silacyclic dipeptides; (3) the cyclized products show a remarkable capacity as substrates of peptide elongation because the silacyclic compounds can act as both nucleophiles and electrophiles, and this capacity lead to one-pot site-selective tetra- and oligopeptide syntheses. These innovative advantages will help to simplify classical peptide synthesis significantly.

Factors Associated with Breakthrough Fungemia Caused by Candida, Trichosporon, or Fusarium Species in Patients with Hematological Disorders

Abstract: Limited data are available on breakthrough fungemia, defined as fungemia that develops on administration of antifungal agents, in patients with hematological disorders. We reviewed the medical and microbiological records of adult patients with hematological diseases who had breakthrough fungemia between January 2008 and July 2019 at Toranomon Hospital and Toranomon Hospital Kajigaya in Japan. ABSTRACT Limited data are available on breakthrough fungemia, defined as fungemia that develops on administration of antifungal agents, in patients with hematological disorders. We reviewed the medical and microbiological records of adult patients with hematological diseases who had breakthrough fungemia between January 2008 and July 2019 at Toranomon Hospital and Toranomon Hospital Kajigaya in Japan. A total of 121 cases of breakthrough fungemia were identified. Of the 121 involved patients, 83, 11, 5, and 22 were receiving micafungin, voriconazole, itraconazole, and liposomal amphotericin B, respectively, when the breakthrough occurred. Of the 121 causative breakthrough fungal strains, 96 were Candida species, and the rest were 13 cases of Trichosporon species, 7 of Fusarium species, 2 of Rhodotorula mucilaginosa, and 1 each of Cryptococcus neoformans, Exophiala dermatitidis, and Magnusiomyces capitatus. The crude 14-day mortality rate of breakthrough fungemia was 36%. Significant independent factors associated with the crude 14-day mortality rate were age of ≥60 years (P = 0.011), chronic renal failure (P = 0.0087), septic shock (P < 0.0001), steroid administration (P = 0.0085), and liposomal amphotericin B breakthrough fungemia (P = 0.0011). An absolute neutrophil count of >500/μL was significantly more common in candidemia in the multivariate analysis (P = 0.0065), neutropenia and nonallogeneic hematopoietic stem cell transplants were significantly more common in Trichosporon fungemia (P = 0.036 and P = 0.033, respectively), and voriconazole breakthrough fungemia and neutropenia were significantly more common in Fusarium fungemia (P = 0.016 and P = 0.016, respectively). The epidemiological and clinical characteristics of breakthrough fungemia of patients with hematological disorders were demonstrated. Some useful factors to predict candidemia, Trichosporon fungemia, and Fusarium fungemia were identified.

Biomimetic Peptide Catalytic Bond-Forming Utilizing a Mild Brønsted Acid.

Abstract: Since the global peptide drug market demand has been predicted to increase, highly efficient and inexpensive mass scale peptides are required. However, the production process raises questions about the cost of energy input, scale-up production, raw materials, and solvents treatment. This paper introduces 2 methods for the 2-4 mer oligopeptides bond formation for batch reaction utilizing 50-100 mol% of a mild Brønsted acid under the mild condition. One of the methods has been capably adapted to flow synthesis at room temperature using organic solvents with boiling points below 100 . The method applies the tert-butoxycarbonyl amino methoxy group, forming the desired dipeptide without solvent at mild temperatures. Furthermore, the conversion of the carboxylic acid leaving the group to phenyl ester promotes peptide bond formation, and the reaction were applied to di, tri, and tetrapeptide bond formation in excellent yield without notable racemization at ambient temperature (up to >99% yield and 99:1 dr). And the end, this study proposes this new production method to overcome the limited scale-up production by reaction device scale: liquid phase biomimetic catalytic peptide flow synthesis utilizing a mild Brønsted acid.

Silicon-based hydrophobic tags applied in liquid-phase peptide synthesis: protected DRGN-1 and poly alanine chain synthesis.

Abstract: Two new recyclable silicon-based hydrophobic tags were developed for installing them at the C-terminal of peptides to increase the solubility in organic solvents and the reactivity of the peptides during liquid-phase peptide synthesis (LPPS). They comprise a siloxy group containing tag and an arylsilyl group containing tag. The hydrophobicity of these tags is much greater than those of previously reported examples. The siloxy group containing tag is compatible with Fmoc-deprotection conditions (Fmoc-chemistry) and hydrogenation conditions (Cbz-chemistry), while the arylsilyl group containing one is resistant to Fmoc-deprotection conditions (Fmoc-chemistry) and Boc-deprotection conditions (Boc-chemistry). Using the siloxy group containing tag, protected DRGN-1, a peptide containing 14 amino acid residues was prepared successfully by using linear synthesis combined with one convergent synthesis step. Using the arylsilyl group containing tag, a poly alanine chain containing 7 alanine residues was synthesized. The arylsilyl group containing tag can also be installed at the N-terminal to elongate the peptides from the N-terminal to the C-terminal. The yields and the solubility of the products in organic solvents in each step were good to excellent with the assistance of these silicon-based tags.

Palladium/Copper-Catalyzed Synthesis of α-Alkenyl α-Amino Acids from 2-Fluoro-1,3-dienes

Abstract: Synergistic Pd/Cu-Catalyzed Csp Bond Alkylation Fluoro-1,3-Dienes

Expeditious Deprotection of N-Benzyloxycarbonyl and N-Benzyl Derivatives

Abstract: © 2 0 2 2 . T h i e m e . A l l r i g h t s r e s e r v e d . G e o r g T h i e m e V e r l a g K G , R ü d i g e r s t r a ß e 1 4 , 7 0 4 6 9 S t u t t g a r t , G e r m a n y M . C . D A G A , M . T A D D E I * , G . V A R C H I ( U N I V E R S I T À D E G L I S T U D I D I S A S S A R I , I T A L Y ) Rapid Microwave-Assisted Deprotection of N-Cbz and N-Bn Derivatives Tetrahedron Lett. 2001, 42, 5191–5194, DOI: 10.1016/S0040-4039(01)00969-8.